Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Current development of mTOR inhibitors as anticancer agents

Nature Reviews Drug Discovery volume 5, pages 671–688 (2006)Cite this article

Key Points

  • Mammalian target of rapamycin (mTOR) is a key kinase that acts as a master switch of cellular catabolism, anabolism, proliferation, cell-cycle control, autophagy, angiogenesis and apoptosis. Human malignancies display a plethora of molecular abnormalities involving phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and/or the PI3K/AKT/mTOR pathway.

  • Rapamycin, a potent mTOR inhibitor, was initially developed as an immunosuppressive agent that, unlike cyclosporine, decreases the risk of post-transplant lymphoproliferative disorders. Both rapamycin itself and rapamycin derivatives (CCI-779, RAD001 and AP23573) have demonstrated antiproliferative and antitumour effects in preclinical models and clinical malignancies.

  • CCI-779 when given weekly as a single agent was the first-in-class mTOR inhibitor to demonstrate survival improvement as compared with interferon in patients with poor-prognosis advanced renal cell carcinoma.

  • Translational studies performed during clinical trials identified molecular markers — p-S6K1 and p-4EBP1 — that were used to monitor biological effects of mTOR inhibitors.

  • Resistance to rapamycin derivatives might result from a lack of AKT activation and/or deficient apoptosis pathways (such as BCL2 expression), and useful biomarkers to predict such therapeutic responses are yet to be discovered.

  • Multitargeting approaches combining other targeted therapy, hormone therapy and/or chemotherapy might improve the therapeutic potential of mTOR derivatives.

Abstract

Mammalian target of rapamycin (mTOR) is a kinase that functions as a master switch between catabolic and anabolic metabolism and as such is a target for the design of anticancer agents. The most established mTOR inhibitors — rapamycin and its derivatives — showed long-lasting objective tumour responses in clinical trials, with CCI-779 being a first-in-class mTOR inhibitor that improved the survival of patients with advanced renal cell carcinoma. This heralded the beginning of extensive clinical programmes to further evaluate mTOR inhibitors in several tumour types. Here we review the clinical development of this drug class and look at future prospects for incorporating these agents into multitarget or multimodality strategies against cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Dysregulation of the PI3K/AKT/mTOR signalling pathway in human cancer.
Figure 2: Effect of mTOR inhibitors on cancer cells.
Figure 3: The effect of modulation of the PI3K/AKT/mTOR pathway with rapamycin derivatives on endothelial and tumour cells.
Figure 4: Antitumour effects of mTOR inhibitors in patients with cancer.
Figure 5: Bench-to-bedside translational research using molecular markers to assess biologically active doses of mTOR inhibitors.
Figure 6: Complexity of the multitargeted approach to cancer therapy.

Similar content being viewed by others

References

  1. Vignot, S., Faivre, S., Aguirre, D. & Raymond, E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann. Oncol. 16, 525–537 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Larue, L. & Bellacosa, A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24, 7443–7454 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Gschwendt, M. Protein kinase Cδ. Eur. J. Biochem. 259, 555–564 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Steinberg, S. F. Distinctive activation mechanisms and functions for protein kinase Cδ. Biochem. J. 384, 449–459 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fang, J. Y. & Richardson, B. C. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 6, 322–327 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Hay, N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 8, 179–183 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Castedo, M., Ferri, K. F. & Kroemer, G. Mammalian target of rapamycin (mTOR): pro- and anti-apoptotic. Cell Death Differ. 9, 99–100 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002). An important review with most references that emphasize PI3K/AKT functions and implications in malignant tumours.

    Article  CAS  Google Scholar 

  9. Inoki, K., Corradetti, M. N. & Guan, K. L. Dysregulation of the TSC–mTOR pathway in human disease. Nature Genet. 37, 19–24 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Johannessen, C. M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl Acad. Sci. USA. 102, 8573–8578 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Luo, Z., Saha, A. K., Xiang, X. & Ruderman, N. B. AMPK, the metabolic syndrome and cancer. Trends Pharmacol. Sci. 26, 69–76 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Shaw, R. J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Lee, L. et al. Efficacy of a rapamycin analog (CCI-779) and IFN-γ in tuberous sclerosis mouse models. Genes Chromosomes Cancer 42, 213–227 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Thomas, G. & Hall, M. N. TOR signaling and control of control of cell growth. Curr. Opin. Cell Biol. 9, 782–787 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Schmelzle, T. & Hall, M. N. TOR, a central controller of cell growth. Cell 103, 253–262 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Guertin, D. A. & Sabatini, D. M. An expanding role for mTOR in cancer. Trends Mol. Med. 11, 353–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Martin, D. E. & Hall, M. N. The expanding TOR signaling network. Curr. Opin. Cell Biol. 17, 158–166 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Scott, P. H. et al. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc. Natl Acad. Sci. USA 95, 7772–7777 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nave, B T. et al. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427–431 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fry, M. J. Phosphoinositide 3-kinase signaling in breast cancer: how big a role might it play? Breast Cancer Res. 3, 304–312 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hu, Q. et al. Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science 268, 100–102 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Lee, A. V. & Yee, D. Insulin-like growth factors and breast cancer. Biomed. Pharmacother. 49, 415–421 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Scheid, M. P. & Woodgett, J. R. Phosphatidylinositol 3′ kinase signaling in mammary tumorigenesis. J. Mammary Gland Biol. Neoplasia 6, 83–99 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Hankinson, S. E. et al. Circulating concentrations of insulin-like growth factor–I and risk of breast cancer. Lancet 351, 1393–1396 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Smith, G. D., Gunnell, D. & Holly, J. Cancer and insulin-like growth factor-I. A potential mechanism linking the environment with cancer risk. BMJ 321, 847–848 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pollack, M. Insulin like growth factor physiology and cancer risk. Eur. J. Cancer 36, 1224–1228 (2000).

    Article  Google Scholar 

  27. Yu, H. & Rohan, T. Role of the insulin-like growth factor family in cancer development and progression. J. Natl Cancer Inst. 92, 1472–1489 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Resnicoff, M. & Baserga, R. The role of the insulin-like growth factor–I receptor in transformation and apoptosis. Ann. NY Acad. Sci. 842, 76–81 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. Cheng, J. Q. et al. Akt2, a putative oncogene encoding a member of a subfamily of serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl Acad. Sci. USA 89, 9267–9271 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cheng, J. Q. et al. Amplification of AKT 2 in human pancreatic cells and inhibition of Akt 2 expression and tumorigenicity by antisense RNA. Proc. Natl Acad. Sci. USA 93, 3636–3641 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bellacosa, A. et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64, 280–285 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001). This paper describes the crucial role of PTEN and PTEN deletions as well as the effects of mTOR inhibitors using in vivo models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brunn, G. J. et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99–101 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Hara, K. et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Chung, J. et al. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 370, 71–75 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Gingras, A. C. et al. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev. 12, 502–513 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brunn, G. J. et al. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 277, 99–101 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR actions. Cell 110, 177–189 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Kim, D.-H. et al. MTOR interacts with raptor to form a nutriement –sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Pain, V. M. Initiation of protein synthesis in eukaryotic cells. Eur. J. Biochem. 236, 747–771 (1996).

    Article  CAS  PubMed  Google Scholar 

  41. Proud, C. G. & Denton, R M. Molecular mechanism for the control of translation by insulin. Biochem. J. 328, 329–341 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sonenberg, N. & Gingras, A. C. The m RNA 5′ cap-binding protein eIF4E and control of cell growth. Curr. Opin. Cell Biol. 10, 268–275 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Smith, M. R. et al. Translation initiation factors induce DNA synthesis and transform NIH 3T3 cells. New Biol. 2, 648–654 (1990).

    CAS  PubMed  Google Scholar 

  44. Rousseau, D. et al. The eIF4E-binding protein 1 and 2 are negative regulators of cell growth. Oncogene 13, 2415–2420 (1996).

    CAS  PubMed  Google Scholar 

  45. Easton, J. B., Kurmasheva, R. T. & Houghton, P. J. IRS-1: auditing the effectiveness of mTOR inhibitors. Cancer Cell 9, 153–155 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Mendez, R. et al. Stimulation of protein synthesis, eukaryotic translation initiation factor 4E phosphorylation and PHAS-I phosphorylation by insulin requires insulin receptor substrate 1 and phosphatidyl inositol 3 kinase. Mol. Cell Biol. 16, 5991–6001 (1996).

    Article  Google Scholar 

  47. Rosenwald, I. B. et al. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J. Biol. Chem. 270, 21176–21180 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Rousseau, D. et al. Translation initiation of ornithine decarboxylase and nuceocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc. Natl Acad. Sci. USA 93, 1065–1070 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Berretta, L. et al. Rapamycin blocks the phos-phorylation of 4E-BP1 and inhibits cap-dependent initiation of translation. EBMO J. 15, 658–664 (1996).

    Google Scholar 

  50. Graves, L. M. et al. c-AMP –and rapamycin-sensitive regulation of the association of eukaryotic initiation factor 4E and the translational regulator PHAS-I in aortic smooth muscle cells. Proc. Natl Acad. Sci. USA 92, 7222–7226 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lin, T. A. et al. Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin — sensitive and mitogen-activated protein kinase-independent pathway. J. Biol. Chem. 270, 18531–18538 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Dilling, B. D. et al. 4E-binding proteins, the suppressors of eukaryotic initiation factor 4E, are down-regulated in cells with acquired or intrinsic resistance to rapamycin. J. Biol. Chem. 277, 13907–13917 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Von Manteuffel, S. et al. 4E-Bp1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase. Proc. Natl Acad. Sci. USA 93, 4076–4080 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Brunn, G. J. et al. Three mammalian target of rapamycin phosphorylates sites having a (Ser/Thr)-Pro motif and is activated by antibodies to a region near its COOH terminus. J. Biol. Chem. 272, 32547–32550 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Fadden, P. Jr. Identification of phosphorylation sites in the translational regulator, PHAS-I, that are controlled by insulin and rapamycin in rat adipocytes. J. Biol. Chem. 272, 10240–10247 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Herbert, P. T., Tee, A. R. & Proud, C. G. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. J. Biol. Chem. 277, 11591–11596 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Di Como, C. J. & Arndt, K. T. Nutrients, via TOR proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev. 10, 1904–1916 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Murata, K., Wu, J. & Brautigan, D. L. B cell receptor-associated protein α4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc. Natl Acad. Sci. USA 148, 71–82 (1997).

    Google Scholar 

  59. Park, I.-H. et al. Regulation of ribosomal S6 kinase 2 by mammalian target of Rapamycin. J. Biol. Chem. 277, 31423–31429 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. Seufferlein, T. & Rozengurt, E. Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res. 56, 3895–3897 (1996).

    CAS  PubMed  Google Scholar 

  61. Brown EJ, Beal PA, Keith CT et al. Control of p70s6 kinase by kinase activity of FRAP in vivo. Nature 377, 441–446 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Burnett, P. E. et al. RAFT 1 phosphorylation of the translational regulators p70 s6 kinase and 4E-BP1. Proc. Natl Acad. Sci. USA 95, 1432–1437 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dennis, P. B. et al. The principal rapamycin-sensitive p70s6k phosphorylation sites T229 and T389 are differentially regulated by rapamycin-insensitive kinase-kinases. Mol. Cell Biol. 16, 6242–6251 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Begum, N. & Ragolia, L. cAMP counter-regulates insulin-mediated protein phosphatase-2A inactivation in rat skeletal muscle cells. J. Biol. Chem. 271, 31166–31171 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Nourse, J. et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372, 570–573 (1994).

    Article  CAS  PubMed  Google Scholar 

  66. Grewe., M. et al. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res. 59, 3581–3587 (1999).

    CAS  PubMed  Google Scholar 

  67. Kawamata, S. et al. The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines. Blood 91, 561–569 (1998).

    CAS  PubMed  Google Scholar 

  68. Hashemolhosseini, S. et al. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J. Biol. Chem. 273, 14424–14429 (1998).

    Article  CAS  PubMed  Google Scholar 

  69. Morice, W. G. et al. Rapamycin inhibition of interleukin-2-dependent p33cdk2 and p34cdc2 kinase activation in T lymphocytes. J. Biol. Chem. 268, 22737–22745 (1993).

    CAS  PubMed  Google Scholar 

  70. Luo, Y. et al. Rapamycin resistance tied to defective regulation of p27Kip1. Mol. Cell. Biol. 16, 6744–6751 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rosenwald, I. B. et al. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J. Biol. Chem. 270, 21176–21180 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Mahajan, P. B. Modulation of transcription of rRNA genes by rapamycin. Int. J. Immunopharmacol. 16, 711–721 (1994).

    Article  CAS  PubMed  Google Scholar 

  73. Leicht, M. et al. Okadaic acid induces cellular hypertrophy in AKR-2B fibroblasts: involvment of the p70S6 kinase in the onset of protein and rRNA synthesis. Cell Growth Differ. 7, 1199–1209 (1996).

    CAS  PubMed  Google Scholar 

  74. White, R. J. Regulation of RNA polymerases I and III by the retinoblastoma protein: a mechanism for growth control? Trends Biochem. Sci. 22, 77–80 (1997).

    Article  CAS  PubMed  Google Scholar 

  75. Rodriguez-Viciana, P. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kanamori, Y. et al. Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma. Clin. Cancer Res. 7, 892–895 (2001).

    CAS  PubMed  Google Scholar 

  78. Uegaki, K. et al. PTEN-positive and phosphorylated-Akt-negative expression is a predictor of survival for patients with advanced endometrial carcinoma. Oncol. Rep. 14, 389–392 (2005).

    CAS  PubMed  Google Scholar 

  79. Soliman, P. T. et al. mTOR inhibition as a potential treatment for progesterone-refractory endometrial hyperplasia. Proc. Am. Soc. Clin. Oncol. 23, 474s, A5080 (2005).

  80. Choe, G. et al. Analysis of the phosphatidylinositol 3-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res. 63, 2742–2746 (2003).

    CAS  PubMed  Google Scholar 

  81. Chakravarti, A. et al. The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas. J. Clin. Oncol. 22, 1926–1933 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Chandrasekar, N. et al. Downregulation of uPA inhibits migration and PI3k/Akt signaling in glioblastoma cells. Oncogene 22, 392–400 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Frisk, T. et al. Silencing of the PTEN tumor-suppressor gene in anaplastic thyroid cancer. Genes Chromosomes Cancer 35, 74–80 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Virolle, T. et al. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nature Cell Biol. 3, 1124–1128 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Tell, G. et al. Control of phosphatase and tensin homolog (PTEN) gene expression in normal and neoplastic thyroid cells. Endocrinology 145, 4660–4666 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Lee, H. Y. et al. Evidence that phosphatidylinositol 3-Kinase-and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J. Biol. Chem. 278, 23630–23638 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Marsit, C. J. et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum. Pathol. 36, 768–776 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Ferraro, B., Bepler, G., Sharma, S., Cantor, A. & Haura, E. B. EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer. J. Clin. Oncol. 23, 1921–1926 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Su, T. H. et al. Mutation analysis of the putative tumor suppressor gene PTEN/MMAC1 in cervical cancer. Gynecol. Oncol. 76, 193–199 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Harima, Y. et al. Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy. Int. J. Oncol. 18, 493–497 (2001).

    CAS  PubMed  Google Scholar 

  91. Cheung, T. H. et al. Epigenetic and genetic alternation of PTEN in cervical neoplasm. Gynecol. Oncol. 93, 621–627 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Tsutsui, S. et al. Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology 68, 398–404 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Shoman, N. et al. Reduced PTEN expression predicts relapse in patients with breast carcinoma treated by tamoxifen. Mod. Pathol. 18, 250–259 (2005).

    Article  CAS  PubMed  Google Scholar 

  94. Saal, L. H. et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65, 2554–2559 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Kirkegaard, T. et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J. Pathol. 207, 139–146 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Saito, M. et al. Allelic imbalance and mutations of the PTEN gene in ovarian cancer. Int. J. Cancer 85, 160–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Levine, D. A. et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. 11, 2875–2878 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Koksal, I. T. et al. The assessment of PTEN tumor suppressor gene in combination with Gleason scoring and serum PSA to evaluate progression of prostate carcinoma. Urol. Oncol. 22, 307–312 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Pfeil, K. et al. Long-term androgen-ablation causes increased resistance to PI3K/Akt pathway inhibition in prostate cancer cells. Prostate 58, 259–268 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Edwards, J., Krishna, N. S., Witton, C. J. & Bartlett, J. M. Gene amplifications associated with the development of hormone-resistant prostate cancer. Clin. Cancer Res. 9, 5271–5281 (2003).

    CAS  PubMed  Google Scholar 

  101. Okami, K. et al. Analysis of PTEN/MMAC1 alterations in aerodigestive tract tumours. Cancer Res. 58, 509–511 (1998).

    CAS  PubMed  Google Scholar 

  102. Kubo, Y., Urano, Y., Hida, Y. & Arase, S. Lack of somatic mutation in the PTEN gene in squamous cell carcinoma of human skin. J. Dermatol. Sci. 19, 199–201 (1999).

    Article  CAS  PubMed  Google Scholar 

  103. Aoki, K. et al. Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma. Oncol. Rep. 11, 375–379 (2004).

    CAS  PubMed  Google Scholar 

  104. Khaleghpour, K., Li, Y., Banville, D., Yu, Z. & Shen, S. H. Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis 25, 241–248 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Velho, S. et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer 41, 1649–1654 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Agbunag, C. & Bar-Sagi, D. Oncogenic K-ras drives cell cycle progression and phenotypic conversion of primary pancreatic duct epithelial cells. Cancer Res. 64, 5659–5663 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Altomare, D. A. et al. Frequent activation of AKT2 kinase in human pancreatic carcinomas. J. Cell Biochem. 88, 470–476 (2003).

    CAS  Google Scholar 

  108. Li, V. S. et al. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 5, 29 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Oki, E. et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int. J. Cancer 117, 376–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  110. Zhang, L., Yu, Q., He, J. & Zha, X. Study of the PTEN gene expression and FAK phosphorylation in human hepatocarcinoma tissues and cell lines. Mol. Cell Biochem. 262, 25–33 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Ma, D. Z. et al. Down-regulation of PTEN expression due to loss of promoter activity in human hepatocellular carcinoma cell lines. World J. Gastroenterol. 11, 4472–4477 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Vezina, C., Kudelski, A. & Sehgal, S. N. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. (Tokyo) 28, 721–726 (1975).

    Article  CAS  Google Scholar 

  113. Yatscoff, R. W., LeGatt, D. F. & Kneteman, N. M. Therapeutic monitoring of rapamycin: a new immunosuppressive drug. Ther. Drug Monit. 15, 478–482 (1993).

    Article  CAS  PubMed  Google Scholar 

  114. Davies, C. B. et al. Effect of a short course of rapamycin, cyclosporin A, and donor-specific transfusion on rat cardiac allograft survival. Transplantation 55, 1107–1112 (1993).

    Article  CAS  PubMed  Google Scholar 

  115. Kahan, B. D. Optimization of cyclosporine therapy. Transplant. Proc. 25, 5–9 (1993).

    CAS  PubMed  Google Scholar 

  116. Trepanier, D. J. et al. Rapamycin: distribution, pharmacokinetics and therapeutic range investigations: an update. Clin. Biochem. 31, 345–351 (1998).

    Article  CAS  PubMed  Google Scholar 

  117. Kauffman, H. M., Cherikh, W. S., Cheng, Y., Hanto, D. W. & Kahan, B. D. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 80, 883–889 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Gallo, R. et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 99, 2164–2170 (1999).

    Article  CAS  PubMed  Google Scholar 

  119. Sousa, J. E. et al. Use of rapamycin-impregnated stents in coronary arteries. Transplant. Proc. 35, 165S–170S (2003).

    Article  CAS  PubMed  Google Scholar 

  120. Mohacsi, P. J. et al. Different inhibitory effects of immunosuppressive drugs on human and rat aortic smooth muscle and endothelial cell proliferation stimulated by platelet-derived growth factor or endothelial cell growth factor. J. Heart Lung Transplant. 16, 484–492 (1997).

    CAS  PubMed  Google Scholar 

  121. Martin, D. E. & Hall, M. N. The expanding TOR signaling network. Curr. Opin. Cell. Biol. 17, 158–166 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet. 36, 585–595 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Li, X., Alafuzoff, I., Soininen, H., Winblad, B. & Pei, J. J. Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J. 272, 4211–4220 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Nardacci, R. et al. Characterization of cell death pathways in human immunodeficiency virus-associated encephalitis. Am. J. Pathol. 167, 695–704 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Castedo, M. et al. Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope. EMBO J. 21, 4070–4080 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Busca, R. et al. Inhibition of the phosphatidylinositol 3-kinase/p70(S6)-kinase pathway induces B16 melanoma cell differentiation. J. Biol. Chem. 271, 31824–31830 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Grewe, M. et al. Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP–p70s6K pathway in human pancreatic cancer cells. Cancer Res. 59, 3581–3587 (1999).

    CAS  PubMed  Google Scholar 

  128. Hosoi, H. et al. Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis in human rhabdomyosarcoma cells. Cancer Res. 59, 886–894 (1999).

    CAS  PubMed  Google Scholar 

  129. Shi, Y. et al. Rapamycin enhances apoptosis and increases sensitivity to cisplatin in vitro. Cancer Res. 55, 1982–1988 (1995).

    CAS  PubMed  Google Scholar 

  130. Calastretti, A. et al., Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase. Oncogene 20, 6172–6180 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Balcarcel, R. R. & Stephanopoulos, G. Rapamycin reduces hybridoma cell death and enhances monoclonal antibody production. Biotechnol. Bioeng. 76, 1–10 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Humar, R. et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J. 16, 771–780 (2002). A report on the role of hypoxia and consequences in activation of cell signalling in endothelial cells, proliferation and tumour angiogenesis.

    Article  CAS  PubMed  Google Scholar 

  133. Castedo, T. et al. Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope. EMBO J. 21, 4070–4080 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Decaudin, D. et al. Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeutic agents. Cancer Res. 57, 62–67 (1997).

    CAS  PubMed  Google Scholar 

  135. Zangemeister-Wittke, U. et al. A novel bispecific antisense oligonucleotide inhibiting both BCL-2 and BCL-xL expression efficiently induces apoptosis in tumor cells. Clin. Cancer Res. 6, 2547–2555 (2000).

    CAS  PubMed  Google Scholar 

  136. Shinjyo, T. et al. Downregulation of bim, a proapoptotic relative of Bcl-2, is a pivotal step in cytokine-initiated survival signaling in murine hematopoietic progenitors. Mol. Cell Biol. 21, 854–864 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Shinoura, N. et al. Expression level of bcl-2 determines anti- or proapoptotic function. Cancer Res. 59, 4119–4128 (1999).

    CAS  PubMed  Google Scholar 

  138. Aguirre, D. et al. Bcl-2 and CCND1/CDK4 expression levels predict the cellular effects of mTOR inhibitors in human ovarian carcinoma. Apoptosis 9, 797–805 (2004). This paper underlines the role of BCL2 expression as a molecular factor of resistance to mTOR inhibitors in human cancer cells.

    Article  CAS  PubMed  Google Scholar 

  139. Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25, 1025–1040 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nature Rev. Cancer. 11, 886–897 (2005).

    Article  Google Scholar 

  141. Hamada, K. et al. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Gene Dev. 19, 2054–2065 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Guba, M. et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Med. 8, 128–135 (2002). Describes the modulation of cross-talk between PI3K/AKT and VEGF signalling pathways by rapamycin.

    Article  CAS  PubMed  Google Scholar 

  143. Humar, R., Kiefer, F. N., Berns, H., Resink, T. J. & Battegay, E. J. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J. 16, 771–780 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Arsham, A. M., Plas, D. R., Thompson, C. B. & Simon, M. C. Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1α nor sufficient for HIF-1-dependent target gene transcription. J. Biol. Chem. 277, 15162–15170 (2002).

    Article  CAS  PubMed  Google Scholar 

  145. Trisciuoglio, D., Iervolino, A., Zupi, G. & Del Bufalo, D. Involvment of PI3K and MAPK signaling in bcl-2-induced vascular endothelial growth factor expression in melanoma cells. Mol. Biol. Cell 16, 4153–4162 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Costa, L. F., Balcells, M., Edelman, E. R., Nadler, L. M. & Cardoso, A. A. Pro-angiogenic stimultation of bone marrow endothelium engages mTOR, and is inhibited by simultaneous blockade of mTOR and NF-κB. Blood 107, 285–292 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Thomas, G. V. et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nature Med. 12, 122–127 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Raymond, E. et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J. Clin. Oncol. 16, 2336–2347 (2004). This paper reports the first-in-man experience (phase I trial) using CCI-779 (temsirolimus, a potent mTOR inhibitor) in patients with advanced cancers, describing the first evidence of antitumour activity in patients with renal cell carcinoma.

    Article  CAS  Google Scholar 

  149. Hidalgo, M. et al. CCI-779, a rapamycin analog and multifaceted inhibitor of signal transduction: a phase I study. Proc. Am. Soc. Clin. Oncol. 19, 187a, A726 (2000).

  150. O'Donnell, A. et al. A phase I study of the oral mTOR inhibitor RAD001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints in patients with solid tumors. Proc. Am. Soc. Clin. Oncol. 22, 200, A803 (2003).

  151. Mita, M. AP23573, an mTOR inhibitor, administered IV daily × 5 every other week in patients with refractory or advanced malignancies — a phase I, pharmacokinetic (PK), and pharmacodynamic (PD) study. Proc. 16th Symp. Mol. Targets Cancer Thera. Geneva, Switzerland, October, 122 A409 (2004).

    Google Scholar 

  152. Oza, A. M. et al. A phase II study or tensirolimus (CCI-779) in patients with metastatic and/or locally recurrent endometrial cancer. Proc. 17th Symp. Mol. Targets Cancer Thera. Philadelphia, USA, November, 197 AB269 (2005).

    Google Scholar 

  153. Galanis, E. et al. Phase II trial of tensirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J. Clin. Oncol. 23, 5294–5304 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Chang, S. M. et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest. New Drugs 23, 357–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Atkins, M. B. et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J. Clin. Oncol. 22, 909–198 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Hudes, G. et al. A phase 3, randomised, 3-arm study of temsirolimus (TEMSR) or interferon-α (IFN) or the combination of TEMSR + IFR in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma. J. Clin. Oncol. 24, Abs. LBA 4, 18S (2006).

    Google Scholar 

  157. Amato, R. J., Misellati, A., Khan, M. & Chiang, S. A phase II trial of RAD001 in patients wih metastatic renal cell carcinoma. J. Clin. Oncol. 24, A4530, 18S (2006).

  158. Chan, S. et al. Phase II study of tensirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J. Clin. Oncol. 23, 5314–5322 (2005).

    Article  CAS  PubMed  Google Scholar 

  159. Witzig, T. E. et al. Phase II trial of single-agent tensirolimus (CCI-779) for relapsed mantle cell lymphoma. J. Clin. Oncol. 23, 5347–5356 (2005). A report of the remarkable antitumour activity of CCI-779 (temsirolimus) in mantle cell lymphoma, a disease driven by cyclin D1 overexpression that can be controlled using mTOR inhibitors.

    Article  CAS  PubMed  Google Scholar 

  160. Ansell, S. M. et al. Anti-tumor activity of mTOR inhibitor temsirolimus for relapse mantle cell lymphoma: a phase II trial in the North Central Cancer Treatment Group. J. Clin. Oncol. 24 18S, A7532 (2006).

  161. Yao, J. C. et al. Phase II study of RAD001 (everolimus) and depot octreotide (sandostatine LAR) in patients with advanced low grade neuroendocrine carcinoma. J. Clin. Oncol. 24, 18S, A4042 (2006).

  162. Duran, I. et al. A phase II trial of temsirolimus in metastatic neuroendocrine carcinoma. Proc. Am. Soc. Clin. Oncol. 24, 824s, A146 (2005).

  163. von Oosterom, A. et al. A phase I/II trial of the oral mTOR-inhibitor everolimus (E) and imatinib mesylate (IM) in patients (pts) with gastrointestinal stromal tumor (GIST) refractory to IM: study update. Proc. Am. Soc. Clin. Oncol. 24, 824s, A9033 (2005).

  164. Chawla, S. P. et al. A phase II trial of AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcoma. Proc. 17th Symp. Mol. Targets Cancer Thera., Philadelphia, USA, November, 268 AC272 (2005).

    Google Scholar 

  165. Boulay, A. et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 64, 252–261 (2004). This research paper reports that S6K1 phosphorylation can be used as a molecular marker for mTOR inhibitors in peripheral blood mononuclear cells, paving the way for the use of S6K1 in translational clinical research.

    Article  CAS  PubMed  Google Scholar 

  166. Duran, I. et al. Pharmacodynamic evaluations of paired tumor biopsies in advanced neuroendocrine carcinomas (NECs) treated with the mTOR inhibitor tensirolimus. Proc. 17th Symp. Mol. Targets Cancer Thera., Philadelphia, USA, November, 230 AC128 (2005).

  167. Paralba, J. M. et al. Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin. Cancer Res. 9, 2887–2892 (2003).

    Google Scholar 

  168. Tabernero, J. et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR inhibitor everolimus (RAD001) in patients (pts) with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. 24, 193s, A3007 (2005).

  169. Reardon, D. A. et al. A phase I trial of AP23573, a novel mTOR inhibitor, in patients (pts) with recurrent malignant glioma. Proc. 17th Symp. Mol. Targets Cancer Thera., Philadelphia, USA, November, 105 AC195 (2005).

  170. Rivera, V. et al. Pharmacodynamic evaluation of the mTOR inhibitor AP23573 in phase I clinical trials. Proc. 16th Symp. Mol. Targets Cancer Thera. Geneva, Switzerland, October, 123 A411 (2004).

  171. Rivera, V. M. et al. Pharmacodynamic study of skin biopsy specimens in patients (pts) with refractory or advanced malignancies following administration of AP23573, an mTOR inhibitor. Proc. Am. Soc. Clin. Oncol. 24, 200s, A3033 (2005).

  172. Sankhala, K. K. et al. Early response evaluation of therapy with AP23573 (an mTOR inhibitor) in sarcoma using [18F]2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scan. Proc. Am. Soc. Clin. Oncol. 24, 823s, A9028 (2005).

  173. Cho, D. C. et al. Low expression of surrogates for mTOR pathway activation predicts resistance to CCI-779 in patients with advanced renal cell carcinoma (RCC). Proc. 17th Symp. Mol. Targets Cancer Thera. Philadelphia, USA, November, 233 C137 (2005).

    Google Scholar 

  174. Diehl, K. M. et al. In-vitro studies of rapamycin treatment of osteosarcoma cell lines. Proc. 17th Symp. Mol. Targets Cancer Thera., Philadelphia, USA, November, 210 AC53 (2005).

    Google Scholar 

  175. Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650–1656 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  PubMed  Google Scholar 

  177. Cheng, J. Q. et al. The Akt/PKB pathway: molecular target for cancer drug discovery. Oncogene 24, 7482–7492 (2005).

    Article  CAS  PubMed  Google Scholar 

  178. Guertin, D. A. & Sabatini, D. M. An expanding role for mTOR in cancer. Trends Mol. Med. 11, 353–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  179. Takeuchi, H. et al. Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 65, 3336–3346 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Sun, S. Y. et al. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 65, 7052–7058 (2005).

    Article  CAS  PubMed  Google Scholar 

  181. Oki, E. et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int. J. Cancer 117, 376–380 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. Aoki, K. et al. Cisplatin activates survival signals in UM-SCC-23 squamous cell carcinoma and these signal pathways are amplified in cisplatin-resistant squamous cell carcinoma. Onc. Rep. 11, 375–379 (2004).

    CAS  Google Scholar 

  183. Beuvink, I. et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 120, 747–759 (2005).

    Article  CAS  PubMed  Google Scholar 

  184. Dong, J. et al. Role of glycogen synthase kinase 3β in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res. 65, 1961–1972 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004). An exploration of the functional role of PTEN for sensitivity to trastuzumab, a HER2 inhibitor, in breast cancer cells.

    Article  CAS  PubMed  Google Scholar 

  186. Kokubo, Y. et al. Reduction of PTEN protein and lss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA). Br. J. Cancer 92, 1711–1719 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Milton, D. T. et al. PhaseI/II trial of gefitinib and RAD001 (everolimus) in patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc. Am. Soc. Clin. Oncol. 24, 646s, A7104 (2005).

  188. deGraffenried, L. A. et al. Inhibition of mTOR activity restores tamoxifene response in breast cancer cells with aberant Akt activity. Clin. Cancer Res. 10, 8059–8067 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Service Inter Hospitalier de Cancrologie (SIHC), Beaujon University Hospital, 100 Boulevard du General Leclerc, Clichy Cedex, 92118, France

    Sandrine Faivre & Eric Raymond

  2. CNRS-UMR 8125, Institute Gustave-Roussy, 39 rue Camille-Desmoulins, Villejuif Cedex, 94805, France

    Guido Kroemer

Authors
  1. Sandrine Faivre
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guido Kroemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Raymond
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric Raymond.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

OMIM

Cowden syndrome

Glossary

Receptor tyrosine kinases

(RTKs). A family of transmembrane receptors that are physiologically activated by the extracellular binding of growth factor(s) and which initiate intracellular signalling, ultimately leading to many cellular responses such as proliferation. Abnormalities of these receptors are often reported in human malignancies.

Translational research

Research aimed at using biological tools for clinical applications.

Glioblastoma

High-grade brain malignancy arising from astrocytes with abnormal cellular proliferation and increased tumour angiogenesis. This cancer is usually refractory to chemotherapy and has a very poor prognosis.

Mucositis

Inflammation and/or ulceration of mouth mucosa.

Thrombocytopaenia

Low level of platelets in circulating blood.

Objective response

Shrinkage of at least 50% of malignant target lesions (according to World Health Organization criteria) after administration of anticancer treatment as compared with baseline measurement.

Sarcoma

Malignant tumour arising from the bone (osteosarcoma) or the soft tissues with high risk of lung metastasis. Patients with soft tissue sarcomas are frequently poor responders to classical chemotherapy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Faivre, S., Kroemer, G. & Raymond, E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 5, 671–688 (2006). https://doi.org/10.1038/nrd2062

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2062

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing